Genetic models of lifespan extension in mammals have not been previously known, and caloric restriction has been the only experimental manipulation shown to retard aging of mammals. We have now demonstrated that overexpression of catalase targeted to mitochondria (MCAT) leads to lifespan extension in mice. Also, we have shown that while overexpression of wild type catalase (targeted to peroxisomes) and Cu-Zn superoxide dismutase (SOD1) have little effect on murine lifespan by themselves, the combination of overexpression of these two produces a significant extension of mean lifespan. These are the first demonstrations that genetically augmented antioxidant defenses can appreciably extend lifespan in mammals. This proposal seeks to extend and better understand these findings. In Aim 1, we will study the physiologic, pathologic and molecular alterations that are responsible for the extended lifespan of MCAT mice. We will compare these changes to those associated with the extended lifespan of calorically restricted mice to determine whether these two mechanisms act through similar or different pathways. In Aim 2, we will build upon our initial observations by creating two improved models of augmented antioxidant protection. We will generate transgenic mice expressing both MCAT and SOD1 from the same promoter and with uniform tissue expression, and we will enhance the redox capacity of MCAT mice by expressing both MCAT and the glutamate-cysteine ligase modulatory subunit (the rate limiting step controlling glutathione synthesis) from the same promoter and with uniform tissue expression. Each model evaluates the benefit of protective mechanisms in different subcellular compartments and/or different antioxidant pathways, and complements the models studied elsewhere in this P01.